Use of 2-methylene-19-nor-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat secondary hyperparathyroidism in patients previously treated with calcimimetics

ABSTRACT

Disclosed are methods of administering 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D 3  to treat and/or prevent secondary hyperparathyroidism and/or its accompanying symptoms in a subject having or at risk for developing secondary hyperparathyroidism, including a subject previously administered a calcimimetic.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application claims the benefit under 35 U.S.C. §119(e) toU.S. Provisional Patent Application No. 62/098,112, filed on Dec. 30,2014, the content of which is incorporated herein by reference in itsentirety.

BACKGROUND

This invention relates to vitamin D compounds useful in treating and/orpreventing secondary hyperparathyroidism and/or the symptoms thereof,and more particularly to the use of the vitamin D compound2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃, otherwise referredto herein as “2MD,” to treat and/or prevent secondaryhyperparathyroidism and/or the symptoms thereof in patients havingsecondary hyperparathyroidism that previously were treated withcalcimimetics.

Secondary hyperparathyroidism refers to the excessive secretion ofparathyroid hormone (PTH) by the parathyroid glands in response tohypocalcemia (low blood calcium levels). This disorder is especiallyseen in patients with chronic renal failure and often is abbreviated as“SHPT” in medical literature.

Renal disease has become an increasingly important health problem invirtually every country in the world including highly developedcountries such as the United States. Presently there are about 250,000patients in the United States on renal dialysis who have lost almostcomplete use of their kidneys. There are approximately ten times morepatients who have lost some degree of renal function due to renaldisease and are progressing to complete renal failure. Renal failure isevidenced by a decreased glomeruli filtration rate (GFR) from a highvalue of 110 ml/minute/1.73 m² to 30 ml/minute/1.73 m² where dialysis isoften initiated, and may be referred to as Stage 5, Chronic KidneyDisease (CKD).

Many factors contribute to the development of renal disease. High bloodpressure is one of the significant contributors, as is having Type I orType II diabetes. Current treatments for renal failure are limited tohemodialysis, an extremely expensive procedure that currently issupported by federal governments because individuals typically cannotafford this procedure on their own. The annual cost of renal disease inthe United States alone is over $42 billion. Accordingly, effectivemethods for preventing renal disease and treating symptoms thereof wouldnot only provide a major health benefit but would also provide a majoreconomic benefit.

Secondary hyperparathyroidism (SHPT) has been successfully managed withthe use of two types of agents: active vitamin D analogs (AVDs) alone orwith the addition of a calcimimetic (CM). Regarding vitamin D's role inmanaging SHPT, it is now universally accepted that vitamin D must firstbe 25-hydroxylated in the liver and subsequently 1α-hydroxylated in thekidney before it can be converted to its active form, namely1α,25-(OH)₂D₃ or “calcitriol.” (See DeLuca, “Vitamin D: The vitamin andthe hormone,” Fed. Proc. 33, 2211-2219, 1974, and DeLuca & Schnoes,“Vitamin D: Recent advances,” Ann. Rev. Biochem. 52, 411-439, 1983).Calcitriol then stimulates a number of physiological processesincluding: stimulating the intestine to absorb calcium, stimulating thekidney to reabsorb calcium, stimulating the intestine to absorbphosphate, and stimulating bone to mobilize calcium when signaled byhigh parathyroid hormone (PTH) levels. These actions result in a rise inplasma calcium and phosphorus levels that bring about the healing ofbone lesions such as rickets and osteomalacia and prevent theneurological disorder of hypocalcemic tetany.

Accordingly, SHPT is a universal complication in patients with chronicrenal failure because patients with chronic renal failure are unable toconvert 25-hydroxyvitamin D₃ from the liver to its active form of1α,25-(OH)₂D₃ via 1α-hydroxylation in the kidney. As a result of lowlevels of circulating 1α,25-(OH)₂D₃ in patients with chronic renalfailure, intestinal calcium absorption is minimal which subsequentlyresults in insufficient serum calcium levels. In addition, duringchronic renal failure, the failing kidneys do not adequately excretephosphate. When this happens, insoluble calcium phosphate forms in thebody and removes calcium from circulation. Ultimately, low levels ofcirculating 1α,25-(OH)₂D₃ and inadequate phosphate excretion contributeto hypocalcemia and secondary hyperparathyroidism because when theparathyroid glands sense a low level of serum calcium (i.e.,hypocalcemia), the parathyroid glands secrete an elevated amount of PTHin order to raise calcium mobilization from bone to raise serum calcium.

In addition to SHPT resulting from renal failure, SHPT also can resultfrom gastrointestinal malabsorption syndromes (e.g., chronicpancreatitis, small bowel disease, and malabsorption-dependent bariatricsurgery in which the intestines do not absorb vitamins and mineralsproperly), where these syndromes are characterized by insufficientabsorption of the fat soluble vitamin D resulting in low levels ofcirculating 1α,25-(OH)₂D₃. Other less common causes of secondaryhyperparathyroidism are long-term lithium therapy, vitamin D deficiency,malnutrition, vitamin D-resistant rickets, or hypermagnesemia (i.e.,abnormally high blood magnesium levels).

As such, overt symptoms of SHPT include increased secretion of PTH. Leftunchecked, the elevated secretion of PTH observed in SHPT will lead tothe development of renal osteodystrophy. High PTH levels can also leadto: 1) weakening of the bones; 2) calciphylaxis (when calcium formsclumps in the skin and lead to ulcers and potentially death ofsurrounding tissue); 3) cardiovascular complications; 4) abnormal fatand sugar metabolism; 5) itching (pruritis); and 6) low blood counts(anemia). Less overt symptoms of SHPT include bone and joint pain, bonedeformities, broken bones (fractures), swollen joints, kidney stones,increased urination, muscle weakness and pain, nausea, loss of appetite,upper abdominal pain, fatigue, and depression.

Because SHPT results from low levels of circulating calcitriol,calcitriol has been administered as a therapeutic in order to supplementthe low levels of circulating calcitriol in patients with SHPT. In thetreatment of SHPT, it is well known that calcitriol binds to the vitaminD receptor (VDR) located in the parathyroid glands to suppress bothgrowth and proliferation of the parathyroid cells and expression of thepreproparathyoid gene. (See Demay et al., “Sequences in the humanparathyroid hormone gene that bind the 1,25-dihydroxyvitamin D₃ receptorand mediate transcriptional repression in response to1,25-hydroxyvitamin D₃.” Proc. Natl. Acad. Sci. USA 89, 8097-8101, 1992;and Darwish & DeLuca. “Identification of a transcription factor thatbinds to the promoter region of the human parathyroid hormone gene,”Arch. Biochem. Biophys. 365, 123-130, 1999). Because of its ability tosuppress parathyroid hormone (PTH), calcitriol has been used withsuccess in the treatment of secondary hyperparathyroidism. (SeeSlatopolsky et al., “Marked Suppression of Secondary Hyperparathyroidismby Intravenous Administration of 1,25-dihydroxycholecalciferol in UremicPatients,” J. Clin. Invest. 74:2136-2143, 1984). However, the use ofcalcitriol in the treatment of SHPT is not without its drawbacks becausecalcitriol may cause hypercalcemia resulting from calcitriol's potentaction on intestinal calcium absorption and bone mineral calciummobilization.

As such, less calcemic analogs of calcitriol that exhibit diminishedactivity on intestinal calcium absorption and/or bone mineral calciummobilization have been developed and have been found to be nearly aseffective as calcitriol in suppressing PTH secretion by cultured bovineparathyroid cells. These include 22-oxacalcitriol (OCT), (Brown et al.,“The Non-Calcemic Analog of Vitamin D, 22-oxacalcitriol (OCT) SuppressesParathyroid Hormone Synthesis and Secretion,” J. Clin. Invest.84:728-732, 1989), as well as 1,25-(OH)₂-16-ene-23-yne-D₃,1,25-(OH)₂-24-dihomo-D₃, and 1,25-(OH)₂-24-trihomo-22-ene-D₃.22-oxacalcitriol has been examined in detail for this action in vivo.(See Brown et al., “Selective Vitamin D Analogs and their TherapeuticApplications,” Sem. Nephrol 14:156-174, 1994, reporting that22-oxacalcitriol, despite its rapid clearance in vivo, could suppressPTH mRNA). Low, submaximal doses of calcitriol and OCT exhibitedcomparable inhibition. OCT also has been shown to suppress serum PTH inuremic rats and dogs.

Another analog of calcitriol with low calcemic and phosphatemic actionis 19-nor-1,25-(OH)₂D₂, which is also known as paricalcitol or19-nor-1α,25-dihydroxy-ergocalciferol. Paricalcitol injection isavailable commercially as Zemplar® from Abbott Laboratories, AbbottPark, Ill. A paricalcitol (Zemplar®) injection is described in U.S. Pat.No. 6,136,799 and has been approved by the FDA and is marketed for theprevention and treatment of secondary hyperparathyroidism associatedwith chronic renal failure (CKD Stage 5 or end-stage renal disease(ESRD), GFR<15 mL/min/1.73 m²).

A newer class of drug used to treat SHPT are the so-called“calcimimetics,” one of which is commercially available as Sensipar®(cinacalcet) in the United States and Australia, and as Mimpara® in theEuropean Union. A calcimimetic (CM) is a drug that mimics the action ofcalcium on the parathyroid gland by allosteric activation of thecalcium-sensing receptor that is expressed in the parathyroid gland. Inparticular, CMs increase the sensitivity of calcium-sensing receptors inthe parathyroid gland and trick the parathyroid gland into thinking thatthere is a sufficient level of serum calcium. As a result of thereceptor thinking that there is sufficient serum calcium, PTH secretionis reduced. Calcimimetics have achieved positive responses and are FDAapproved for use in patients on dialysis, but have not been approved foruse in chronic kidney disease pre-dialysis because, among otherconcerns, CMs also can increase phosphorus levels. Further, CMs causehypocalcemia and are provided together with a vitamin D analog (AVD) toboth prevent hypocalcemia and to help in suppression of serum PTH. OftenCMs are employed when an AVD by itself is unable to suppress the PTHwithout also causing hypercalcemia. Thus, both a CM and an AVD may beadministered to treat SHPT in some patient.

Thus, a drug for treating SHPT that can suppress PITH with minor effectson calcium and phosphate metabolism would be an ideal tool for thecontrol and treatment of secondary hyperparathyroidism. Here, a highlypotent active vitamin D analog (AVD), namely,2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃, referred to hereinas “2MD”, is shown to suppress PTH production while maintaining serumcalcium and serum phosphate in the normal range. (See also U.S.Published Application No. 2014/0005152, the content of which isincorporated herein by reference in its entirety). As such, 2MD may beuseful for treating SHPT in patients that previously were treated withother AVDs or calcimimetics (CMs).

SUMMARY

It has now been discovered that the vitamin D analog2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) has the abilityto treat secondary hyperparathyroidism as well as symptoms of secondaryhyperparathyroidism when administered under well-controlled conditionsto a subject in need thereof, including a subject previously treatedwith a calcimimetic (CM). It also now been discovered that the vitamin Danalog 2MD has the ability to prevent secondary hyperparathyroidism aswell as symptoms of secondary hyperparathyroidism when administeredunder well-controlled conditions to a subject in need thereof, includinga subject previously requiring a calcimimetic and an active vitamin Danalog (AVD). Thus, 2MD has the unique property among vitamin Dcompounds to eliminate or reduce the need for a CM in the management ofsecondary hyperparathyroidism.

In one embodiment, the present invention provides a novel method oftreating secondary hyperparathyroidism by administering atherapeutically effective amount of a composition comprising2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) orpharmaceutically acceptable salts thereof as the active agent to asubject exhibiting symptoms of secondary hyperparathyroidism, includinga subject previously treated with a calcimimetic, preferably withoutinducing hypercalcemia in the subject.

In another embodiment, the present invention provides a novel method oftreating symptoms of secondary hyperparathyroidism by administering atherapeutically effective amount of a composition comprising2-methylene-19-nor-(20S)-1α,25-dihyroxyvitamin D₃ (2MD) orpharmaceutically acceptable salts thereof as the active agent to asubject exhibiting symptoms of secondary hyperparathyroidism, includinga subject previously treated with a calcimimetic, preferably withoutinducing hypercalcemia in the subject.

In yet another embodiment, the present invention provides a novel methodof preventing secondary hyperparathyroidism by administering atherapeutically effective amount of a composition comprising2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) orpharmaceutically acceptable salts thereof as the active agent to asubject at risk of developing secondary hyperparathyroidism, including asubject previously treated with a calcimimetic, preferably withoutinducing hypercalcemia in the subject.

In still another embodiment, the present invention provides a novelmethod of preventing symptoms of secondary hyperparathyroidism byadministering a therapeutically effective amount of a compositioncomprising 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) orpharmaceutically acceptable salts thereof as the active agent to asubject at risk of developing secondary hyperparathyroidism, including asubject previously treated with a calcimimetic, preferably withoutinducing hypercalcemia in the subject.

In the disclosed methods, the2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) may beformulated in an oral, topical, transdermal, parenteral, injectable orinfusable form of a pharmaceutical composition comprising a suitabledose of 2MD. In some embodiments, pharmaceutical compositions maycomprise 2MD (or pharmaceutically acceptable salts thereof) in a minimaldose of at least about 0.01, 0.05, 0.1, 0.5, 1.0, 5.0, 10.0, 50.0,100.0, 500.0 or 1000.0 μg/gm of the composition. In other embodiments,pharmaceutical compositions may comprise 2MD (or pharmaceuticallyacceptable salts thereof) in a maximal dose no greater than 1000.0,500.0, 100.0, 50.0, 10.0, 5.0, 1.0, 0.1, or 0.05 μg/gm of thecomposition. The compositions may comprise 2MD within dose ranges havingas end-points any of these disclosed doses (e.g., where 2MD represents0.01-1000.0 μg/gm of the composition). Minimal and/or maximal doses maybe administered at any suitable frequency, such as daily, three timesper week, weekly, or other frequencies.

Patients suitable for the disclosed treatment and prevention methods mayinclude a patient having or at risk for developing secondaryhyperparathyroidism or the symptoms thereof including a patientpreviously administered a calcimimetic. For example, patients suitablefor the disclosed treatment and prevention methods may include a patientpreviously administered cinacalcet.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Change in plasma iPTH (%) versus concentration of DP001 (2MD).Chronic kidney disease-stage 5 patients were given DP001 at theindicated dose orally 3 times weekly for 4 weeks. Data are presented asmean±SEM. Plasma iPTH levels were measured using the Immulite IntactiPTH Assay from Siemens Healthcare Diagnostics.

FIG. 2. Safety parameter versus concentration of DP001 (2MD) forpatients of FIG. 1. Data are presented as mean (standard deviation(SD)).

FIG. 3. Study schema for study participants. Participants discontinueduse of the active vitamin D analogue (AVD) and cinacalcet (ifapplicable) prior to a washout period and subsequent administration ofplacebo or DP001 (440 ng, 3×/wk, for up to 12 weeks).

FIG. 4. Subject disposition tree.

FIG. 5. Demographic and baseline characteristics of study enrollees.

FIG. 6. Percentage of subjects achieving primary endpoint of twoconsecutive ≧30% decrease from his/her averaged baseline iPHT levelduring the 12-week treatment period. Pre-dialysis serum iPTH levels weremeasured using the Access Intact iPTH Assay from Beckman Coulter(p<0.0001, Fisher's exact test).

FIG. 7. Secondary efficacy endpoint as measured as the mean percentagechange in serum iPTH from the averaged baseline value to the average ofthe last 2 on-treatment values. Data are presented as mean±SEM.p<0.0001, One-way ANOVA.

FIG. 8. Change in PTH from averaged baseline (%) for “All Patients,”“Patients Previously on Active Vitamin D Analogue (AVD) only,” and“Patients on AVD and Cinacalcet” administered placebo or DP001.

FIG. 9. Study enrollees exceeding safety threshold values for iPTH, Ca,and P.

FIG. 10. Number of adverse events (AEs) and serious adverse events(SAEs) for study enrollees.

DETAILED DESCRIPTION

Disclosed are methods of treating and/or preventing secondaryhyperparathyroidism or the symptoms thereof, including treating and/orpreventing secondary hyperparathyroidism and/or the symptoms thereof ina subject previously treated with a calcimimetic. The disclosed methodsfurther may described as follows based on the following definitions.

As used in this specification and the claims, the singular forms “a,”“an,” and “the” include plural forms unless the content clearly dictatesotherwise. For example, “an active vitamin D compound” or “AVD,” shouldbe interpreted to mean “one or more AVDs,” and “a calcimimetic” or “CM”should be interpreted to mean “one or more CMs.”

As used herein, “about”, “approximately,” “substantially,” and“significantly” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which they are used.If there are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” and“approximately” will mean up to plus or minus 10% of the particular termand “substantially” and “significantly” will mean more than plus orminus 10% of the particular term.

As used herein, the terms “include” and “including” have the samemeaning as the terms “comprise” and “comprising.” The terms “comprise”and “comprising” should be interpreted as being “open” transitionalterms that permit the inclusion of additional components further tothose components recited in the claims. The terms “consist” and“consisting of” should be interpreted as being “closed” transitionalterms that do not permit the inclusion additional components other thanthe components recited in the claims. The term “consisting essentiallyof” should be interpreted to be partially closed and allowing theinclusion only of additional components that do not fundamentally alterthe nature of the claimed subject matter.

As used herein, the term “patient,” which may be used interchangeablywith the terms “subject” or “individual,” refers to one who receivesmedical care, attention or treatment and may encompass a human patient.The disclosed methods may be utilized to treat and/or prevent secondaryhyperthyroidism of the symptoms thereof in a patient in need thereof,including a patient previously treated with a calcimimetic. A patient inneed thereof may include, but is not limited to, a patient having or atrisk for developing secondary hyperthyroidism subsequent to a renaldisease or disorder, including a patient previously treated with acalcimimetic. A patient in need thereof may include, but is not limitedto, a patient having or at risk for developing secondary hyperthyroidismsubsequent to renal osteodystrophy, for example, due to renal failure,including a patient previously treated with a calcimimetic. A patient inneed thereof may include a patient undergoing renal dialysis, includinga patient previously treated with a calcimimetic. A patient in needthereof may include, but is not limited to, a patient having or at riskfor developing secondary hyperthyroidism as a result of agastrointestinal malabsorption syndromes (e.g., chronic pancreatitis,small bowel disease, and malabsorption-dependent bariatric surgery inwhich the intestines do not absorb vitamins and minerals properly),including a patient previously treated with a calcimimetic. A patient inneed thereof may include, but is not limited to, a patient having or atrisk for developing secondary hyperthyroidism as a result of a long-termlithium therapy, vitamin D deficiency, malnutrition, vitamin D-resistantrickets, or hypermagnesemia (i.e., abnormally high blood magnesiumlevels), including a patient previously treated with a calcimimetic.

The disclosed methods may be utilized to treat and/or prevent thesymptoms of secondary hyperthyroidism in a patient in need thereof,including a patient previously treated with a calcimimetic. Symptoms ofsecondary hyperthyroidism treated and/or prevented by the disclosedmethods may include, but are not limited to: increased levels of serumPTH, serum phosphorus, and serum creatinine. Other symptoms of secondaryhyperthyroidism treated and/or prevented by the disclosed methods mayinclude: weakening of the bones; calciphylaxis (when calcium formsclumps in the skin and lead to ulcers and potentially death ofsurrounding tissue); cardiovascular complications; abnormal fat andsugar metabolism; itching (pruritis); and low blood counts (anemia).Further symptoms of secondary hyperthyroidism treated and/or preventedby the disclosed methods may include: bone and joint pain, bonedeformities, broken bones (fractures), swollen joints, kidney stones,increased urination, muscle weakness and pain, nausea, and loss ofappetite. Even further symptoms of secondary hyperthyroidism treatedand/or prevented by the disclosed methods may include: fatigue, upperabdominal pain, and depression.

Previously, it has been demonstrated that calcitriol administeredthrough the diet can effectively prevent renal disease and renal failureby reducing the symptoms of renal disease. (See James Wonkee Kim.Effects of calcitriol on the MRL/MpJ-fas/lpr model of systemic lupuserythematosus (Ph.D. Thesis, University of Wisconsin-Madison (2009)).For instance, it has been previously shown that administering calcitriolcompletely prevents proteinuria in the MRL/MpJ-FAS^(lpr) (MRL/lpr) mousemodel of systemic lupus erythematosus (SLE). (See id.). However, severehypercalcemia always accompanied this treatment. Hypercalcemia (i.e.,increased levels of calcium in the blood) can result in serious physicalproblems, including death. Specifically, an increase in calcium ofapproximately 2 mg/100 ml is considered mild hypercalcemia and is notconsidered a problem. However, an increase in calcium levels of morethan 2 mg/100 ml is considered severe hypercalcemia and can causecalcification of the kidney, heart, and aorta. Clearly, the use of thiscompound is not optimal to treat or prevent secondaryhyperparathyroidism, or the symptoms thereof, because of the resultanthypercalcemia.

2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) is an analog of1,25(OH)₂D₃ which has been shown to have increased in vivo potencytoward bone but not on intestinal calcium absorption. The overallsynthesis of 2MD is illustrated and described more completely in U.S.Pat. No. 5,843,928, issued Dec. 1, 1998, and entitled“2-Alkylidene-19-Nor-Vitamin D Compounds” the specification of which isspecifically incorporated herein by reference. The biological activityof 2MD is also reported in U.S. Pat. No. 5,843,928 and in Shevde et al,“A Potent Analog of 1α,25-dihydroxyvitamin D₃ Selectively Induces BoneFormation” PNAS, Vol. 99, No. 21 pp 13487-13491 (2002), both of whichare specifically incorporated herein by reference.

Surprisingly, in the methods disclosed herein, 2MD can be administeredto treat and/or prevent secondary hyperparathyroidism and/or itsaccompanying symptoms preferably without causing severe hypercalcemia ina patient in need thereof, including a patient previously treated with acalcimimetic. As used herein, “hypercalcemia” means elevated calciumlevels in the blood. In a normal subject, calcium levels areapproximately 9-10.5 mg/dL or 2.2-2.6 mmol/L. As such, calcium levelsgreater than about 10.5 mg/dL or 2.6 mmol/L may be indicative ofhypercalcemia. In cases of severe hypercalcemia (i.e., calcium levelsabove 15-16 mg/dL or 3.75-4 mmol/L) coma and cardiac arrest can develop.In the methods disclosed herein, 2MD can be administered to treat and/orprevent secondary hyperparathyroidism and/or its accompanying symptomsincluding elevated PTH levels, elevated phosphorus levels, and elevatedcreatinine levels.

Also in the methods disclosed herein, 2MD can be used to treat andreduce the severity of secondary hyperparathyroidism of renal diseaseand its accompanying symptoms in a patient in need thereof, including apatient previously treated with a calcimimetic, preferably withoutcausing severe hypercalcemia, by reducing PTH, phosphorus, andcreatinine levels in blood.

The present invention therefore provides novel methods of treatingand/or preventing secondary hyperparathyroidism and/or its accompanyingsymptoms in a subject at risk of developing secondaryhyperparathyroidism, and of treating and/or preventing secondaryhyperparathyroidism and/or its accompanying symptoms in a subjectexhibiting symptoms of secondary hyperparathyroidism, by administeringto the subject a therapeutically effective amount of2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ (2MD) orpharmaceutically acceptable salts thereof preferably without inducinghypercalcemia in the subject, where 2MD has the structure (I):

The disclosed methods may include administering 2MD to a patient thatpreviously was administered a calcimimetic (e.g., in order to treatand/or prevent secondary hyperparathyroidism and/or the symptomsthereof). In some embodiments of the disclosed methods, after 2MD isadministered to the patient, administration of the calcimimetic isdiscontinued. In other embodiments of the disclosed methods, the patientis administered 2MD and a calcimimetic (e.g., in order to treat and/orprevent secondary hyperparathyroidism and/or the symptoms thereof). Forexample, 2MD may be administered to the patient before, concurrently, orafter the calcimimetic is administered to the patient.

As utilized herein, a calcimimetic is an agent that mimics the effect ofcalcium on the parathyroid gland. As such, calcimimetics increase thesensitivity of the calcium-sensing receptor (CaR) to circulating serumcalcium, reducing the secretion of PTH and the serum calciumconcentration. Calcimimetics may include, but are not limited to thecompound named(R)—N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amineotherwise referred to as “cinacalcet.”

As used herein, “preventing” means forestalling of a clinical symptomindicative of secondary hyperparathyroidism. Such forestalling includes,for example, the maintenance of normal kidney functions in a subject atrisk of developing secondary hyperparathyroidism prior to thedevelopment of overt symptoms of secondary hyperparathyroidismincluding, but not limited to, increased levels of serum PTH, phosphorusand creatinine. Therefore, the term “preventing” includes theprophylactic treatment of subjects to guard them from the occurrence ofsecondary hyperparathyroidism. Preventing secondary hyperparathyroidismin a subject is also intended to include inhibiting or arresting thedevelopment of secondary hyperparathyroidism. Inhibiting or arrestingthe development of secondary hyperparathyroidism includes, for example,inhibiting or arresting the occurrence of increased levels of serum PTH,phosphorus and creatinine.

As used herein, a “renal disease” or a “renal disorder” means acondition exhibiting impaired kidney function in a subject who is not ondialysis or a patient with chronic kidney disease (CKD) at stages 2 or3, such as, for instance, acute kidney failure, acute nephriticsyndrome, analgesic nephropathy, atheroembloic renal disease, chronickidney failure, chronic nephritis, congenital nephrotic syndrome,goodpasture syndrome, interstitial nephritis, kidney cancer, kidneydamage, kidney infection, kidney injury, kidney stones,membranoproliferative GNI, membranoproliferative GNII, membranousnephropathy, minimal change disease, necrotizing glomerulonephritis,nephroblastoma, nephrocalcinosis, nephrogenic diabetes insipidus,nephropathy-IgA, nephrosis nephrotic syndrome, polycystic kidneydisease, post-strepococcal GN, reflux nephropathy, renal arteryembolism, renal artery stenosis, renal disorders, renal papillarynecrosis, renal tubular acidosis type I, renal tubular acidosis type II,renal underperfusion, renal vein thrombosis.

“Renal disease” is meant to include patients with established kidneyfailure (e.g., a glomerular filtration rate (GFR) of less than 15mL/min/1.73 m² or permanent renal replacement therapy (RRT)). A subjecthaving “renal disease” is meant to include a subject who has had kidneydamage for more than 3 months, as defined by structural or functionalabnormalities of the kidney, with or without decreased GFR, manifestedby either pathological abnormalities or markers of kidney damage,including abnormalities in the composition of the blood or urine, orabnormalities in imaging tests. Markers of kidney damage includeproteinuria of greater than 300 μg/day as measured by 24-HR excretionmethod. (Sec Table 15, Am. J. of Kidney Diseases, v. 39, no. 2, Suppl. 1(February 2002), pp. 546-575, incorporated herein by reference). Thisdefinition may include patients on dialysis.

As used herein, a patient having “stage 2 chronic kidney disease (CKD)”means a patient exhibiting a mild reduction in GFR (60-89 mL/min/1.73m²). Kidney damage is defined as pathologic abnormalities or markers ofdamage, including abnormalities in blood or urine test or imagingstudies. A patient having “stage 3 chronic kidney disease (CKD)” means apatient exhibiting a moderate reduction in GFR (30-59 mL/min/1.73 m²).Guidelines for characterizing kidney disease may distinguish betweenstage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screeningand referral. For more information about stages of kidney disease, seeAm. J. of Kidney Disease, V. 39, No. 2, Suppl. 1, February 2002,incorporated herein by reference. “Renal failure” is evidenced by adecreased glomeruli filtration rate (GFR) from a high value of 110ml/minute/1.73 m² to 30 ml/minute/1.73 m² where dialysis is ofteninitiated, and may be referred to as Stage 5, Chronic Kidney Disease(CKD).

As used herein, “administering” mean introducing a compound into thebody, preferably into the systemic circulation, as described in moredetail below. Examples include but are not limited to oral, topical,buccal, sublingual, pulmonary, transdermal, transmucosal, as well assubcutaneous, intraperitoneal, intravenous, and intramuscular injectionor in the form of liquid or solid doses via the alimentary canal.

As used herein, “therapeutically effective” means an amount of acompound that, when administered to a subject for treating or preventinga disease, is sufficient to effect such treatment of prevention of thedisease. A “therapeutically effective amount” will vary depending on thecompound, the disease state being treated, the severity or the diseasetreated, the age and relative health of the subject, the route and formof administration, the judgment of the attending medical or veterinarypractitioner, and other factors.

Pharmaceutical compositions for use in the disclosed treatment andprevention methods comprise an effective dose of 2MD as an activeingredient and a suitable carrier. An effective dose of 2MD for use inaccordance with the disclosed methods is high enough for achieving adesired therapeutic effect and low enough so as not as to cause anundesired side effect (e.g., hypercalcemia). In some embodiments,pharmaceutical composition may comprise 2MD in a minimal dose of atleast about 0.01, 0.05, 0.1, 0.5, 1.0, 5.0, 10.0, 50.0, 100.0, 500.0 or1000.0μ/gm of the composition. In other embodiments, pharmaceuticalcomposition may comprise 2MD in a maximal dose no greater than 1000.0,500.0, 100.0, 50.0, 10.0, 5.0, 1.0, 0.1, 0.05 μg/gm of the composition.The compositions may comprise 2MD within dose ranges having asend-points any of these disclosed doses (e.g., 0.01-1000.0 μg/gm of thecomposition). Minimal and/or maximal doses may be administered at anysuitable frequency, such as daily, three times per week, weekly, orother frequencies.

In the disclosed treatment and prevention methods, a patient in needthereof may be administered an effective dose level of 2MD. An effectivedose level of 2MD for use in accordance with the disclosed methods ishigh enough for achieving a desired therapeutic effect and low enough soas not as to cause an undesired side effect (e.g., hypercalcemia). Insome embodiments, a minimal dose level for achieving therapy may be atleast about 0.1, 0.25, 0.5, 1.0, 2.5, 5.0, 10.0, 12.5, 15.0, or 20.0ng/kg body weight of the subject. In some embodiments, a maximal doselevel may not exceed about 20.0, 15.0, 12.5, 10.0, 5.0, 2.5, 1.0, 0.5,0.25, and 0.1 ng/kg body weight of the subject. Minimal and/or maximaldose levels may include dose level ranges having as end-points any ofthese discloses dose levels (e.g., 0.1-20.0 ng/kg body weight of thesubject).

As used herein, “treat,” “treating” or “treatment” means amelioration,alleviation or ablation of a clinical symptom indicative of secondaryhyperparathyroidism. Amelioration, alleviation or ablation of a clinicalsymptom includes, for example, arresting, reducing the severity of orslowing the progression of or causing the regression of a symptom ofsecondary hyperparathyroidism. For instance, lowering the amount ofserum PTH, serum phosphorus or serum creatinine levels in response totreatment with 2MD. Specifically, treating may include reducing theamount of serum PTH, serum phosphorus or serum creatinine pre-treatmentversus post-treatment by at least about 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or more. Other pathological conditions, chronic complicationsor phenotypic manifestations of secondary hyperparathyroidism are knownto those skilled in the art and can similarly be used as a measure oftreating secondary hyperparathyroidism so long as there is a reductionin the severity of the condition, complication or manifestationassociated with the disease.

Effective compound formulations of 2MD are described in U.S. Pat. No.5,843,928 and include pharmaceutical applications as a solution ininnocuous solvents, or as an emulsion, suspension or dispersion insuitable solvents or carriers, or as pills, tablets, capsules combinedwith solid carriers. Other formulations may also include otherpharmaceutically acceptable and nontoxic excipients such as stabilizers,anti-oxidants, binders, coloring agents or emulsifying ortaste-modifying agents and extended release formulations.

In one embodiment, 2MD is the active pharmaceutical ingredient (API)administered in the disclosed methods. The API may be formulated in anoral pharmaceutical dosage form as a solution in innocuous solvents,emulsion, suspension or dispersion in suitable solvents or carriers. TheAPI may also be formulated in various oral dosage forms, such as pills,tablets or capsules using suitable pharmaceutical solid carriers. Suchpharmaceutical formulations may also contain other pharmaceuticallysuitable USP-approved inactive ingredients, excipients, such asstabilizers, anti-oxidants, binders, coloring agents, emulsifiers,and/or taste-modifying agents, which are referred to as USP approvedinactive pharmaceutical ingredients.

The API may be administered orally, topically, parenterally ortransdermally or by inhalation. The compound may be administered byinjection or intravenous infusion using suitable sterile solutions.Topical dosage forms may be creams, ointments, patches, or similarvehicles suitable for transdermal and topical dosage forms. Preferablyfor the treatment of secondary hyperparathyroidism, or for the treatmentor prevention of the symptoms of secondary hyperparathyroidism, thecompound 2MD is administered either orally or parenterally (i.v.). Thedose may be properly selected in accordance with the specific route ofadministration. In some embodiments, the patient may be administered adose as low as 55 ng, 110 ng, 220 ng, 330 ng, 440 ng, 550 ng, or 660 ng,daily or 3 times per week in order to treat secondaryhyperparathyroidism and/or to treat or prevent the symptoms thereof in apatient. In some embodiments, the patient may be administered a dose ashigh as 110 ng, 220 ng, 330 ng, 440 ng, 550 ng, 660 ng, or 770 ng, dailyor 3 times per week in order to treat secondary hyperparathyroidismand/or to treat or prevent the symptoms thereof in a patient. Minimaland/or maximal doses may include dose ranges having as end-points any ofthese disclosed doses (e.g., 55 ng-770 ng).

The pharmaceutically suitable oral carrier systems (also referred to asdrug delivery systems, which are modern technology, distributed with oras a part of a drug product that allows for the uniform release ortargeting or drugs to the body) preferably include FDA-approved and/orUSP-approved inactive ingredients. Under 21 CFR 210.3(b)(8), an inactiveingredient is any component of a drug product intended to furnishpharmaceutical activity or other direct effect in the diagnosis, or toaffect the structure or any function of the body of humans or otheranimal. Active ingredients include those components of the product thatmay undergo chemical change during the manufacture of the drug productand be present in the drug product in a modified form intended tofurnish the specified activity or effect. As used herein, a kit (alsoreferred to as a dosage form) is a packaged collection of relatedmaterial.

As used herein, “oral dosage” forms may include capsules (i.e., a solidoral dosage form consisting of a shell and a filling), whereby the shellis composed of a single sealed enclosure, or two halves that fittogether and which are sometimes sealed with a band, and whereby capsuleshells may be made from gelatin, starch, or cellulose, or other suitablematerials, may be soft or hard, and are filled with a solid or liquidingredients that can be poured or squeezed. The oral dosage form mayalso be a capsule or coated pellets, in which the drug is enclosedwithin either a hard or soft soluble container or “shell” made from asuitable form of gelatin. The drug itself may be in the form of granulesto which varying amount of coating have been applied or in a capsulecoated extended release, in which the drug is enclosed within either ahard or soft soluble container or “shell” made from a suitable form ofgelatin. Additionally, the capsule may be covered in a designatedcoating which releases a drug or drugs in such a manner to allow atleast a reduction in dosing frequency as compared to that drug or drugspresented as a conventional dosage form.

The oral dosage form may further be a capsule delayed release, in whichthe drug is enclosed within either a hard or soft soluble container madefrom a suitable form of gelatin, and which releases a drug (or drugs) ata time other than promptly after administration, whereby enteric-coatedarticles are delayed release dosage forms. Capsule delayed releasepellets, in which the drug is enclosed within either a hard or softcontainer or “shell” are also useful. In these cases, the drug itself isin the form of granules to which enteric coating has been applied, thusdelaying release of the drug until its passing into the intestine.Capsule extended release and capsule film-coated extended release arealso useful.

Additionally, the capsule is covered in a designated film coating, andwhich releases a drug or drugs in such a manner to allow at least areduction in dosing frequency as compared to that drug or drugspresented as a conventional dosage form), capsule gelatin coated (asolid dosage form in which the drug is enclosed within either a hard orsoft soluble container made from a suitable form of gelatin; through abanding process, the capsule is coated with additional layers of gelatinso as to form a complete seal), capsule liquid filled (a solid dosageform in which the drug is enclosed within a soluble, gelatin shell whichis plasticized by the addition of a polyol, such as sorbitol orglycerin, and is therefore of a somewhat thicker consistency than thatof a hard shell capsule).

Typically, the active ingredients may be dissolved or suspended in aliquid vehicle, a granule (a small particle or grain), a pellet (a smallsterile solid mass consisting of a highly purified drug, with or withoutexcipients, made by the formation of granules, or by compression andmolding), or a pellet coated extended release (a solid dosage form inwhich the drug itself is in the form of granules to which varyingamounts of coating have been applied, and which releases a drug or drugsin such a manner to allow a reduction in dosing frequency as compared tothat drug or drugs presented as a conventional dosage form).

Other forms include pills (a small, round solid dosage form containing amedicinal agent intended for oral administration), powder (an intimatemixture of dry, finely divided drugs and/or chemicals that may beintended for internal or external use), elixir (a clear, pleasantlyflavored, sweetened hydroalcoholic liquid containing dissolved medicinalagents; it is intended for oral use), chewing gum (a sweetened andflavored insoluble plastic material of various shapes which when chewed,releases a drug substance into the oral cavity), syrup (an oral solutioncontaining high concentrations of sucrose or other sugars; the term hasalso been used to include any other liquid dosage form prepared in asweet and viscid vehicle, including oral suspensions), tablet (a soliddosage form containing medicinal substances with or without suitablediluents), tablet chewable (a solid dosage form containing medicinalsubstances with or without suitable diluents that is intended to bechewed, producing a pleasant tasting residue in the oral cavity that iseasily swallowed and does not leave a bitter or unpleasant after-taste),tablet coated or tablet delayed release, tablet dispersible, tableteffervescent, tablet extended release, tablet film coated, or tabletfilm coated extended release where the tablet is formulated in suchmanner as to make the contained medicament available over an extendedperiod of time following ingestion.

In other forms, a tablet for solution, tablet for suspension, tabletmultilayer, tablet multilayer extended release may be provided, wherethe tablet is formulated in such manner as to allow at least a reductionin dosing frequency as compared to that drug presented as a conventionaldosage form. A tablet orally disintegrating, tablet orallydisintegrating delayed release, tablet soluble, tablet sugar coated,osmotic, and the like are also suitable.

The oral dosage form composition may contain an active pharmaceuticalingredient and one or more inactive pharmaceutical ingredients such asdiluents, solubilizers, alcohols, binders, controlled release polymers,enteric polymers, disintegrants, excipients, colorants, flavorants,sweeteners, antioxidants, preservatives, pigments, additives, fillers,suspension agents, surfactants (e.g., anionic, cationic, amphoteric andnonionic), and the like. Various FDA-approved topical inactiveingredients are found at the FDA's “The Inactive Ingredients Database”that contains inactive ingredients specifically intended as such by themanufacturer, whereby inactive ingredients can also be considered activeingredients under certain circumstances, according to the definition ofan active ingredient given in 21 CFR 210.3(b)(7). Alcohol is a goodexample of an ingredient that may be considered either active orinactive depending on the product formulation.

As used herein, the injectable and infusion dosage forms include, butare not limited to, a liposomal injectable, which either consists of orforms liposomes (a lipid bilayer vesicle usually composed ofphospholipids which is used to encapsulate an active drug substance). Aninjection, which includes a sterile preparation intended for parenteraluse; five distinct classes of injections exist as defined by the USP, isalso suitable. An emulsion injection, which includes an emulsionconsisting of a sterile, pyrogen-free preparation intended to beadministered parenterally or a lipid complex injection are alsosuitable.

Other forms include a powder for solution injection, which is a sterilepreparation intended for reconstitution to form a solution forparenteral use: a powder for suspension injection that is a sterilepreparation intended for reconstitution to form a suspension forparenteral use; a powder lyophilized for liposomal suspension injection,which is a sterile freeze dried preparation intended for reconstitutionfor parenteral use which has been formulated in a manner that wouldallow liposomes (a lipid bilayer vesicle usually composed ofphospholipids which is used to encapsulate an active drug substance,either within a lipid bilayer or in an aqueous space) to be formed uponreconstitution; a powder lyophilized for solution injection, which is adosage form intended for the solution prepared by lyophilization(“freeze drying”), a process which involves the removal of water fromproducts in the frozen state at extremely low pressures.

This is intended for subsequent addition of liquid to create a solutionthat conforms in all respects to the requirements for injections; apowder lyophilized for suspension injection being a liquid preparation,intended for parenteral use that contains solids suspended in a suitablefluid medium and conforms in all respects to the requirements forSterile Suspensions; the medicinal agents intended for the suspensionare prepared by lyophilization (“freeze drying”), a process whichinvolves the removal of water from products in the frozen state atextremely low pressures; a solution injection being a liquid preparationcontaining one or more drug substances dissolved in a suitable solventor mixture of mutually miscible solvents that is suitable for injection;a solution concentrate injection being a sterile preparation forparenteral use which, upon the addition of suitable solvents, yields asolution conforming in all respects to the requirements for injections.

A suspension injection comprises a liquid preparation, suitable forinjection, which consists of solid particles dispersed throughout aliquid phase in which the particles are not soluble that can alsoconsist of an oil phase dispersed throughout an aqueous phase, orvice-versa. A suspension liposomal injection comprises a liquidpreparation, suitable for injection, which consists of an oil phasedispersed throughout an aqueous phase in such a manner that liposomes (alipid bilayer vesicle usually composed of phospholipids which is used toencapsulate an active drug substance, either within a lipid bilayer orin an aqueous space) are formed. A suspension sonicated injectioncomprises a liquid preparation, suitable for injection, which consistsof solid particles dispersed throughout a liquid phase in which theparticles are not soluble. In addition, the product is sonicated while agas is bubbled through the suspension, and this results in the formationof microspheres by the solid particles.

The parenteral carrier system includes one or more pharmaceuticallysuitable excipients, such as solvents and co-solvents, solubilizingagents, wetting agents, suspending agents, thickening agents,emulsifying agents, chelating agents, buffers, pH adjusters,antioxidants, reducing agents, antimicrobial preservatives, bulkingagents, protectants, tonicity adjusters, and special additives.Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the active ingredientwhich is preferably isotonic with the blood of the recipient.

As used herein, inhalation dosage forms include, but are not limited to,aerosol being a product that is packaged under pressure and containstherapeutically active ingredients that are released upon activation ofan appropriate valve system intended for topical application to the skinas well as local application into the nose (nasal aerosols), mouth(lingual and sublingual aerosols), or lungs (inhalation aerosols); foamaerosol being a dosage form containing one or more active ingredients,surfactants, aqueous or nonaqueous liquids, and the propellants, wherebyif the propellant is in the internal (discontinuous) phase (i.e., of theoil-in-water type), a stable foam is discharged, and if the propellantis in the external (continuous) phase (i.e., of the water-in-oil type),a spray or a quick-breaking foam is discharged, metered aerosol being apressurized dosage form consisting of metered dose valves which allowfor the delivery of a uniform quantity of spray upon each activation;powder aerosol being a product that is packaged under pressure andcontains therapeutically active ingredients, in the form of a powder,that are released upon activation of an appropriate valve system; and,aerosol spray being an aerosol product which utilizes a compressed gasas the propellant to provide the force necessary to expel the product asa wet spray and being applicable to solutions of medicinal agents inaqueous solvents.

As used herein, transdermal dosage forms include, but are not limitedto, a patch being a drug delivery system that often contains an adhesivebacking that is usually applied to an external site on the body, wherebythe ingredients either passively diffuse from, or are activelytransported from, some portion of the patch, and whereby depending uponthe patch, the ingredients are either delivered to the outer surface ofthe body or into the body; and, other various types of transdermalpatches such as matrix, reservoir and others known in the art.

As used herein, topical dosage forms include various dosage forms knownin the art such as lotions (an emulsion, liquid dosage form, wherebythis dosage form is generally for external application to the skin),lotion augmented (a lotion dosage form that enhances drug delivery,whereby augmentation does not refer to the strength of the drug in thedosage form), gels (a semisolid dosage form that contains a gellingagent to provide stiffness to a solution or a colloidal dispersion,whereby the gel may contain suspended particles) and ointments (asemisolid dosage form, usually containing less than 20% water andvolatiles and greater than 50% hydrocarbons, waxes, or polyols as thevehicle, whereby this dosage form is generally for external applicationto the skin or mucous membranes).

Ointment augmented (an ointment dosage form that enhances drug delivery,whereby augmentation does not refer to the strength of the drug in thedosage form), creams (an emulsion, semisolid dosage form, usuallycontaining greater than 20% water and volatiles and/or less than 50%hydrocarbons, waxes, or polyols may also be used as the vehicle, wherebythis dosage form is generally for external application to the skin ormucous membranes. Cream augmented (a cream dosage form that enhancesdrug delivery, whereby augmentation does not refer to the strength ofthe drug in the dosage form), emulsions (a dosage form consisting of atwo-phase system comprised of at least two immiscible liquids, one ofwhich is dispersed as droplets, internal or dispersed phase, within theother liquid, external or continuous phase, generally stabilized withone or more emulsifying agents, whereby emulsion is used as a dosageform term unless a more specific term is applicable, e.g. cream, lotion,ointment), suspensions (a liquid dosage form that contains solidparticles dispersed in a liquid vehicle), suspension extended release,pastes (a semisolid dosage form, containing a large proportion, 20-50%,of solids finely dispersed in a fatty vehicle, whereby this dosage formis generally for external application to the skin or mucous membranes),solutions (a clear, homogeneous liquid dosage form that contains one ormore chemical substances dissolved in a solvent or mixture of mutuallymiscible solvents), and powders are also suitable.

Jellies (a class of gels, which are semisolid systems that consist ofsuspensions made up of either small inorganic particles or large organicmolecules interpenetrated by a liquid—in which the structural coherentmatrix contains a high portion of liquid, usually water) and films (athin layer or coating), including film extended release (a drug deliverysystem in the form of a film that releases the drug over an extendedperiod in such a way as to maintain constant drug levels in the blood ortarget tissue) and film soluble (a thin layer or coating which issusceptible to being dissolved when in contact with a liquid) are alsosuitable.

Patches (a drug delivery system that often contains an adhesive backingthat is usually applied to an external site on the body, whereby itsingredients either passively diffuse from, or are actively transportedfrom, some portion of the patch, whereby depending upon the patch, theingredients are either delivered to the outer surface of the body orinto the body, and whereby a patch is sometimes synonymous with theterms ‘extended release film’ and ‘system’), patch extended release (adrug delivery system in the form of a patch that releases the drug insuch a manner that a reduction in dosing frequency compared to that drugpresented as a conventional dosage form, e.g., a solution or a promptdrug-releasing, conventional solid dosage form), patch extended releaseelectronically controlled (a drug delivery system in the form of a patchwhich is controlled by an electric current that releases the drug insuch a manner that a reduction in dosing frequency compared to that drugpresented as a conventional dosage form, e.g., a solution or a promptdrug-releasing, conventional solid dosage form), and the like. Thevarious topical dosage forms may also be formulated as immediaterelease, controlled release, sustained release, or the like.

The topical dosage form composition contains an active pharmaceuticalingredient and one or more inactive pharmaceutical ingredients such asexcipients, colorants, pigments, additives, fillers, emollients,surfactants (e.g., anionic, cationic, amphoteric and nonionic),penetration enhancers (e.g., alcohols, fatty alcohols, fatty acids,fatty acid esters and polyols), and the like. Various FDA-approvedtopical inactive ingredients are found at the FDA's “The InactiveIngredients Database” that contains inactive ingredients specificallyintended as such by the manufacturer, whereby inactive ingredients canalso be considered active ingredients under certain circumstances,according to the definition of an active ingredient given in 21 CFR210.3(b)(7). Alcohol is a good example of an ingredient that may beconsidered either active or inactive depending on the productformulation.

EXAMPLES

The following examples are presented for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.The examples illustrate that 2MD, an analog of 1,25(OH)₂D₃ originallythought to be important in prevention and treatment of osteoporosis, isalso important in preventing and treating secondary hyperparathyroidismand its accompanying symptoms in a patient in need thereof including apatient previously treated with a calcimimetic.

Title: 2MD, A New Treatment for Secondary Hyperparathyroidism: A Phase2B, Double-Blind, Randomized, Placebo-Controlled Study in HemodialysisPatients

Reference is made to “2MD, A New Treatment for SecondaryHyperparathyroidism: A Phase 2B, Double-Blind, Randomized,Placebo-Controlled Study in Hemodialysis Patients,” Hector F. DeLuca,Julia B. Zella, Danielle C. Knutson, Lori A. Plum, and MargaretClagett-Dame, Poster Presentation at the 2014 American Society ofNephrology, Kidney Week Meeting, November 2014.

Background

Secondary hyperparathyroidism (SHPT) has been successfully managed withthe use of active vitamin D analogs (AVDs) alone, or with the additionof a calcimimetic (CM). However, both classes of compounds havedrawbacks. Hypercalcemia is of concern when AVDs are used, while CMs cancause hypocalcemia and have compliance issues because of nausea andvomiting. A novel, highly potent AVD(2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3, 2MD or DP001)specifically targets the parathyroid glands and bone and is beingdeveloped for the treatment of SHPT in patients on hemodialysis.

Study and Results

Dose Selection.

A Phase 2A, open-label, dose-ranging study of DP001 in hemodialysispatients was conducted to determine a starting dose of DP001 for thePhase 2B, randomized, placebo-controlled study described in thisExample. Given orally 3 times weekly for 4 weeks, DP001 suppresses PTHin dialysis patients in a dose-dependent fashion without changing serumcalcium. (See FIGS. 1 and 2). Based on the results in FIGS. 1 and 2, anefficacious and safe starting dose of 440 ng was chosen. Data arepresented as mean±SEM. Plasma iPTH levels were measured using theImmulite Intact iPTH Assay from Siemens Healthcare Diagnostics.

Eligibility Criteria.

Subjects in the study met the following eligibility criteria: men andnon-pregnant women ≧18 years of age; exhibiting end stage renal disease(ESRD) or chronic kidney disease (CKD) stage 5 (GFR<15 mL/min/1.73 m²))and on hemodialysis 3×/week ≧3 months; prior active vitamin D userequired; prior cinacalcet use allowed but not required; first screen:Ca≦10.5 mg/dL, P≦7.0 mg/dL, iPTH≦500 pg/mL; final screen: Ca≦9.8 mg/dL,P≦6.5 mg/dL, iPTH≧300 pg mL; vitamin D₂ or D₃ limited to ≦4000 IU/day(or equivalent); P binders allowed but class must stay consistent; andno severe heart or liver problems, active malignancies or infections,calciphylaxis, or PTx.

Study.

Subjects were administered DP001 (2MD) or placebo accordingly the studyschema of FIG. 3. Subject disposition is illustrated in FIG. 4. Asindicated, 129 subject were screened. Of these, 62 were enrolled and 67were screen failures. Of the 62 enrollees, 28 were administered aplacebo and 34 were administered DP001 (440 ng, 3×/wk for up to 12weeks). Of the 28 enrollees who were administered the placebo, 22completed the 12 week study and 6 discontinued for reasons illustrated.Of the 34 enrollees who were administered DP001, 31 completed the 12week study and 3 discontinued for reasons illustrated.

Demographics and Baseline Characteristics.

The demographics and baseline characteristics of the subjects enrolledin the study are presented in FIG. 5.

Primary Efficacy Endpoint.

The primary efficacy endpoint was the proportion of subjects whoachieved two consecutive ≧30% decrease from his/her Averaged BaselineiPTH level during the 12-week treatment period. (See FIG. 6).Pre-dialysis serum iPTH levels were measured using the Access IntactiPTH Assay from Beckman Coulter (p<0.0001, Fisher's exact test).

Secondary Efficacy Endpoint.

The secondary efficacy endpoint was the mean percentage change in serumiPTH from the Averaged Baseline value to the average of the last 2on-treatment values. Data are presented in FIG. 7 as mean±SEM. p<0.0001,One-way ANOVA.

DP001 Alone Lowers iPTH in CKD-5D Patients Previously on Cinacalcet.

As illustrated in FIG. 8, DP001 (2MD) effectively reduced PTH levels insubject previously being treated with an active vitamin D analogue (AVD)and a calcimimetic (CM) in the form of cinacalcet.

Safety Results—Endpoints.

Safety results and endpoints are presented in FIG. 9. Of the 14 subjectsthat reached the safety threshold for PTH, 6 had been dose-adjusteddownward following an upward adjustment, suggesting insufficient timewas allotted for PTH levels to respond to DP001 (2MD). The remaining 8subjects were only dose-adjusted downward, indicating a starting doselower than 440 ng would have been sufficient to suppress PTH. Thecorrected-serum calcium and phosphorus product safety threshold wassurpassed in two patients that also had high serum phosphorus values atbaseline (7.8 mg/dL and 9.4 mg/dL), suggesting that phosphorushomeostasis was difficult to manage in these patients even before anyexposure to DP001 (2MD). Only one patient receiving DP001 (2MD) had twoconsecutive corrected serum calcium values >10.5 mg/dL.

Safety Results—Adverse Events.

Safety results and adverse events (AEs) are presented in FIG. 10. Noserious adverse events (SAEs) were judged by the investigators to berelated to DP001.

SUMMARY AND CONCLUSIONS

A novel analog (2MD or DP001) of calcitriol that selectively targets theparathyroid gland is being developed for the treatment of secondaryhyperparathyroidism (SHPT) in subjects having chronic kidney diseasesstage 5 (CKD-5D). In the Phase 2B double-blind, placebo-controlledstudy, 3× weekly oral DP001 reduced serum iPTH by 46% in 78% of subjectsby 12 weeks of treatment (p<0.0001), satisfying both primary andsecondary endpoints. DP001 alone successfully treats SHPT in patientspreviously taking a calcimimetic. There were no significant differencesin adverse event reporting between treatment groups. Serum calciumvalues remained in the normal range, and changes in serum phosphoruswere similar between Placebo and DP001 groups.

In the foregoing description, it will be readily apparent to one skilledin the art that varying substitutions and modifications may be made tothe invention disclosed herein without departing from the scope andspirit of the invention. The invention illustratively described hereinsuitably may be practiced in the absence of any element or elements,limitation or limitations which is not specifically disclosed herein.The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention that in theuse of such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention. Thus, it should be understood that although the presentinvention has been illustrated by specific embodiments and optionalfeatures, modification and/or variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All publications and patentsspecifically mentioned herein are incorporated by reference in theirentirety for all purposes including describing and disclosing thechemicals, instruments, statistical analyses and methodologies which arereported in the publications which might be used in connection with theinvention. All references cited in this specification are to be taken asindicative of the level of skill in the art. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue or prior invention.

Citations to a number of references are made herein. The citedreferences are incorporated by reference herein in their entireties. Inthe event that there is an inconsistency between a definition of a termin the specification as compared to a definition of the term in a citedreference, the term should be interpreted based on the definition in thespecification.

We claim:
 1. A method of treating secondary hyperparathyroidism or thesymptoms thereof in a subject having secondary hyperparathyroidism or atrisk for developing secondary hyperparathyroidism, wherein the subjectpreviously was administered a calcimimetic to treat the secondaryhyperparathyroidism, the method comprising administering atherapeutically effective amount of2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ or a pharmaceuticallyacceptable salt thereof to the subject wherein secondaryhyperparathyroidism or the symptoms thereof are treated.
 2. The methodof claim 1, wherein secondary hyperparathyroidism is treated withoutinducing hypercalcemia in the subject.
 3. The method of claim 1, whereinthe therapeutically effective amount ranges from about 0.5 ng/kg toabout 20 ng/kg.
 4. The method of claim 1, wherein the therapeuticallyeffective amount ranges from about 1.0 ng/kg to about 10 ng/kg.
 5. Themethod of claim 1, wherein the subject is administered thetherapeutically effective amount daily.
 6. The method of claim 1,wherein the subject is administered the therapeutically effective amountthree times per week.
 7. The method of claim 1, wherein the2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ is formulated in anoral, topical, transdermal, parenteral, injection or infusion dosageform.
 8. The method of claim 1, wherein the subject has chronic kidneydisease-stage 5 (CKD-5D) and is receiving hemodialysis treatment.
 9. Themethod of claim 1, wherein the symptoms of secondary hyperparathyroidismare selected from the group consisting of elevated serum PTH, elevatedserum phosphorus, and elevated serum creatinine.
 10. The method of claim1, wherein after administering the therapeutically effective amount of2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃ to the subject, thesubject is not administered any calcimimetic.
 11. The method of claim 1,further comprising administering a therapeutically effective amount of acalcimimetic to the subject.
 12. The method of claim 1, wherein thetherapeutically effective amount of the calcimimetic is administeredconcurrently with the therapeutically effective amount of2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D₃.